Nucleotide sequence comparison of five human pepsinogen A (PGA) genes: evolution of the PGA multigene family

To unravel the genetic basis for the pepsinogen A (PGA) protein polymorphism, we have isolated and characterized a number of PGA genes, distinguishable by polymorphic EcoRI fragments of 12.0, 15.0, and 16.6 kb. Using a HindIII or AvaII polymorphism, we can discriminate between different 15.0 (15.0 and 15.0*) and 12.0 (12.0s and 12.0l) genes, respectively. The coding sequences of a 15.0 and a 16.6 gene were determined, together with considerable stretches of the 5'- and 3'-flanking regions and introns. The genes were demonstrated to encode Pg5 and Pg4, respectively. Because substitutions in codons 43 and 207 appeared to be critical in the determination of the encoded proteins, we sequenced only these regions in the two 12.0 genes and the 15.0* gene. On the basis of these partial sequences, we assume that these genes encode Pg3. In the evolutionary model of the PGA gene cluster presented here, the 12.0 genes arose by an unequal, but homologous crossover. The results of sequence analysis of the second intron of the 12.0s, 12.0l, 15.0, and 16.6 genes suggest that the two 12.0 genes have arisen from two different crossover events.